Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillations-a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal γ oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases γ oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for γ oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in γ oscillation power. This unique link between D4R and ErbB4 signaling on γ oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and γ oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.     

Plant secondary siRNA production determined by microRNA-duplex structure

Processing of microRNA (miRNA) precursors results in the release of a double-stranded miRNA/miRNA* duplex. The miRNA or guide strand, is loaded onto the Argonaute (AGO) effector, and the miRNA* or passenger strand is typically degraded. The loaded AGO-containing RNA-induced silencing complex specifically recognizes a target mRNA, leading to its degradation or translational inhibition. In plants, miRNA-mediated cleavage of a target triggers in some cases the production of secondary small interfering RNAs (siRNAs), which in turn can silence other genes in trans. This alternative pathway depends on the length of the miRNA and the specific AGO in the effector complex. However, 22-nt miRNAs are sufficient, but not essential for this pathway. Using a combination of computational and experimental approaches, we show that transitivity can be triggered when the small RNA that is not retained in AGO is 22-nt long. Moreover, we demonstrate that asymmetrically positioned bulged bases in the miRNA:miRNA* duplex, regardless of miRNA or miRNA* length, are sufficient for the initiation of transitivity. We propose that the RNA-induced silencing complex reprogramming occurs during the early steps of miRNA loading, before the miRNA duplex is disassembled and the guide strand is selected.     

Transabdominal preperitoneal versus totally extraperitoneal repair of inguinal hernia: a meta-analysis of randomized studies

Background

The aim of the present study was to comparatively evaluate the outcomes of laparoscopic transabdominal preperitoneal inguinal hernia repair and totally extraperitoneal repair.

Methods

The electronic databases of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, and a meta-analysis of randomized clinical trials was undertaken.

Results

Seven studies comprising 516 patients with 538 inguinal hernia defects were identified. A shorter recovery time (P = .02) was found for totally extraperitoneal repair in comparison with transabdominal preperitoneal inguinal hernia repair (weighted mean difference = −.29; 95% confidence interval [CI], −.71 to .07) although the length of hospitalization (P = .89) was similar in the 2 treatment arms (weighted mean difference = .01; 95% CI, −.13 to .15). Operative morbidity (P = .004) was higher for the preperitoneal approach (odds ratio = 2.15; 95% CI, 1.29 to 3.61). No differences were found with regard to the incidence of recurrence, long-term neuralgia, and operative time.

Conclusions

Current evidence suggests similar operative results for endoscopic and laparoscopic inguinal hernia repair, with a trend toward higher morbidity for the preperitoneal approach. Randomized trials with a longer-term follow-up are needed in order to assess the effect of each approach on the prevention of recurrence.     

Outcome of surgery for ileojejunal neuroendocrine tumors

Purpose

Neuroendocrine tumors (NET) of the ileum/jejunum are rare and may require different treatment options to provide long-term survival. The purpose of the study was to evaluate the outcome of surgery for ileojejunal NET.

Methods

A database of patients that underwent surgery for ileojejunal NETs between 1999 and 2010 was retrospectively analyzed regarding the clinical characteristics, surgical therapy, survival and prognostic factors.

Results

Only six of 97 patients with ileojejunal NET who underwent surgery had localized tumors (stage I/II), 29 had lymph node involvement (stage III) and 62 had distant metastases (stage IV) at the initial presentation. All stage I/II tumors were cured, in comparison to 69 % of stage III and 0 % of stage IV tumors (p = 0.01). Palliative surgery in combination with sequential multimodal treatment regimens resulted in a 5-year survival rate of 63 % in patients with stage IV tumors. A multivariate analysis showed that incomplete resection (HR 2.87; CI 1.18–6.98; p = 0.04) and distant metastases (HR 5.39; 95 % CI 1.23–23.57; p = 0.02) were associated with worse disease-specific survival.

Conclusions

Localized and regionally restricted ileojejunal NETs have an excellent prognosis after surgical treatment. Although stage IV tumors cannot be cured, an aggressive surgical approach in combination with medical or interventional treatment can provide long-term survival.     

Salvage radiotherapy in patients with persistently detectable PSA or PSA rising from an undetectable range after radical prostatectomy gives comparable results

Purpose

Salvage radiotherapy (SRT) is applied routinely in patients with a biochemical relapse after radical prostatectomy (RP). Although the detection threshold for relapse after RP has steadily been lowered, only about 30 % of the SRT patients achieve a durable response. We have previously shown the association between a PSA decrease below detectable levels after SRT and biochemical progression-free survival (BPFS). After recalculating our data according to a more recent definition of biochemical failure after SRT, we now show the significance of the post-RP PSA nadir.

Materials and methods

Among 159 prostate cancer patients without hormonal treatment after RP, SRT was given to 72 patients with persistently detectable PSA after RP and to 87 whose PSA increased out of an undetectable range. The median pre-SRT PSA was 0.29 ng/ml for the former group and 0.34 ng/ml for the latter group. A radiation dose of 66.6 Gy was applied to the prostate bed.

Results

The overall median follow-up time was 41.7 months. The probability for BPFS after this period was 52.8 % in 72 patients with persistently detectable PSA after RP and 65.4 % in 87 patients who had a post-RP PSA nadir below detection limit. Univariate and multivariate analyses showed no significant difference in BPFS of both patient groups (p > 0.05).

Conclusion

Our findings suggest that SRT is a viable treatment option for patients with persistently detectable PSA, giving similar results as in patients whose PSA increases out of an undetectable range after RP.     

Relevance of Bilateral Cervical Thymectomy in Patients with Renal Hyperparathyroidism: Analysis of 161 Patients Undergoing Reoperative Parathyroidectomy

Background

The most frequent location of ectopic or supernumerary inferior parathyroid is the thymus. Bilateral cervical thymectomy has therefore been recommended as an essential part of the initial surgery for renal hyperparathyroidism (rHPT) to avoid persistent or recurrent cervical disease. The aim of this study was to evaluate how often reoperation might have been avoidable if an appropriate cervical thymectomy had been performed during initial surgery.

Methods

A prospective database of patients with rHPT was screened for patients on permanent dialysis who underwent reoperative parathyroidectomy (PTX) between 1976 and 2010. Data were retrospectively analyzed for the performance of bilateral cervical thymectomy during previous surgeries and the presence of ectopic and/or supernumerary intrathymic parathyroid glands during reoperative PTX.

Results

Of 161 patients who underwent reoperative PTX, 95 had neck reexploration. Among them were 29 patients with total PTX and autotransplantation, seven with subtotal PTX (3.5 glands resected), and 59 with incomplete PTX during the initial surgery. Bilateral cervical thymectomy during the initial PTX was performed in only 12 of 95 patients (12.6 %). It was revealed to be incomplete in six of them, inheriting an intrathymic parathyroid gland during reoperative interventions. Reoperative PTX revealed intrathymic parathyroid glands in 27 of 95 patients (28.4 %). The intrathymic parathyroid glands were ectopic in 17 (63.0 %) patients and supernumerary in 8 (29.6 %). Both ectopic and supernumerary intrathymic parathyroid glands were found in two patients (7.4 %).

Conclusions

The risk for persistent and recurrent disease based on intrathymic parathyroid glands is a relevant problem during initial surgery for rHPT. Thus, routine bilateral cervical thymectomy that is as complete as possible is essential during the initial PTX for rHPT.     

Attentional processing in adults with ADHD as reflected by event-related potentials

Attention deficit/hyperactivity disorder (ADHD) is a well known childhood disease and well researched via event-related potentials (ERPs), but unfortunately there is little information on this illness in adults in ERPs. In the present study, 12 adults diagnosed with ADHD and 12 healthy control adults were examined with respect to ERPs in a visual Go/NoGo-experiment to gain information about target evaluation processing in these patients. Two attention-related ERP-components, the N1 and N2 were significantly increased for the ADHD adults compared to the healthy control adults. These findings were illustrated using source analysis results: In the time frame corresponding to the N1, significant increases of activity were found in the medial frontal gyrus and during the N2 time frame significant increases were detected in the lingual gyrus. The P300 showed a tendency towards decreased activity in the patient group, however, only a subsequent slow wave activity indicated significant differences. Neuronal activity related to early attentional mechanisms (N1 and N2) appears to be enhanced in ADHD patients. Together with the finding of a reduction in the P300, the data suggest that ADHD adults have learned to gather their attention more strongly than healthy adults in order to achieve the same results and compensate for their impairment. This is supported by the source analysis results which show activity in additional brain areas.     

The contribution of B cells to renal interstitial inflammation

Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system.     

The role of interstitial macrophages in nephropathy of type 2 diabetic db/db mice

Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.     

Transoral parathyroid surgery—a new alternative or nonsense?

Purpose

In recent years, several endoscopic techniques have been explored in thyroid and parathyroid surgery, but only few gained acceptance among patients and surgeons. Based on extensive human cadaver and animal studies, we developed a technique for transoral partial parathyroidectomy (TOPP), which was performed for the first time in a patient with primary hyperparathyroidism (pHPT). We now report on results and the acceptance of this new technique 2 years after its implementation.

Methods

A pilot study was initiated to recruit a total of 10 patients with benign sporadic pHPT and a preoperatively localized parathyroid adenoma eligible for initial parathyroidectomy. The study protocol was approved by the ethics committee, and an insurance for unforeseen complications and risks was procured. Data of all patients evaluated and operated were prospectively collected, and follow-up examinations were carried out for 19 months on average, which included clinical examinations; ultrasonography; Ear, Nose, and Throat (ENT) investigations; and blood testing.

Results

Between January 2010 and May 2012, 75 patients with pHPT and a preoperative localized parathyroid adenoma were eligible for TOPP. After detailed information about the transoral procedure, only five (7 %) female patients consent to undergo TOPP. In three patients, a parathyroid adenoma could be removed via the transoral access, In two patients, the procedure had to be converted to the conventional technique. Median time until resection of a parathyroid adenoma was 122 min (range, 45–175). One patient had a transient recurrent laryngeal nerve palsy, while one patient suffered from a transient palsy of the right hypoglossal nerve and a slight but persisting dysgeusia. Three patients developed a hematoma of the mouth floor and swallowing problems. In four patients, the visual analog scale (VAS) pain score was high (>7) within the first 2 postoperative days.

Conclusions

Although TOPP is feasible, it is poorly accepted by patients and its complication rate is high. Thus, TOPP is nonsense with currently available devices.